Excess sugars in the diabetic milieu induce proteins with slow turnover to accumulate yellow and fluorescent modifications which may serve as markers for a person's past glycemic history and potential for future complications. The objective is to elucidate the biochemical nature of skin auto-fluorescence that has been widely used in the diabetes literature as a presumptive and recently proposed noninvasive marker for advanced glycation end-product "AGE"-formation. In 1993, this laboratory was able to obtain skin biopsies from 216 participants with type 1 diabetes in the DCCT study and quantitate various AGE markers of glycemic exposure and damage. Strong correlations between skin levels and severity of micro-vascular disease as well as decrease in skin levels of AGEs were noted in subjects undergoing intensive vs. conventional therapy for hyperglycemia. Four and eight years later, these associations were reevaluated in the EDIC trial, and to our surprise, several of the markers were found to predict the risk of progression of retinopathy and nephropathy. Most surprisingly, however, only one marker of unknown chemical origin named "collagen-linked long-wavelength fluorescence" ("LW') was found to predict the risk of calcium deposition and atherosclerosis progression as measured by coronary artery calcium deposition "CAC" at all CAC scores; i.e., >0, >100, and >200. Specific aims are: (1) elucidate the structure of the novel marker of atherosclerosis progression yet elusive fluorophore "LW" in skin ; (2) To quantitate LW in skin biopsy collagen obtained at the time of DCCT closeout, and determine its ability to predict risk of macro- and micro-vascular disease in the EDIC; (3) To determine the quantitative relationship between LW in skin and carotid artery and the in situ relationship between LW formation and calcium deposition in autopsy tissue from individuals with diabetes and end-stage renal disease; and (4) to determine the in vivo mechanism of LW-1 formation and prevention of formation in animal models of diabetes and hyperlipidemia. Because LW fluorescence can be monitored non-invasively in cornea and skin, this research may have broad implications for the development of novel methodologies for assessment of the risk for macro-vascular disease progression in diabetes. [unreadable]